Vitamin E is comprised of eight different antioxidant compounds found in nature; four tocopherols and four tocotrienols. These two families differ from each other in the structure of the side chain, which is saturated in tocopherols and has three double bonds in the tocotrienols. The distinguishing feature within each family is the number and position of methyl groups attached to the chroman ring.
The tocopherols, namely α-tocopherol, β-tocopherol, γ-tocopherol and δ-tocopherol, are understood to be the major lipid soluble compounds in mammalian membranes. They act as chain-breaking inhibitors of free radical peroxidation of unsaturated fatty acids. Despite the fact that the diets of most North American individuals contain more γ-tocopherol than α-tocopherol, it is predominantly α-tocopherol that is retained in the body due to actions of a specific binding and transfer protein known as the tocopherol transfer protein (TTP). TTP is expressed mostly in liver tissue and has been shown to specifically bind α-tocopherol. The function of TTP is to aid in the secretion of the vitamin in lipoproteins such as very-low-density-lipoprotein that then carry the vitamin to remote tissues of the body. Interestingly, the other forms of vitamin E, besides α-tocopherol, are poorly retained by the body and are rapidly metabolized to water-soluble compounds for excretion in urine or transported to bile.
The metabolism of non-retained tocopherols (i.e., non-α-tocopherol and tocotrienols) is initiated in human cells by a cytochrome P450 monooxygenase, Cyp4F2, and its orthologs in other species. The enzyme activity is referred to as tocopherol-ω-hydroxylase. This enzyme metabolizes all forms of vitamin E by placing a hydroxyl group at the terminus of the side chain.
Recently it has been noted that γ-tocopherol and the tocotrienols have biological activities that are different from α-tocopherol. γ-tocopherol is known to act as an anti-inflammatory possibly by mechanisms different than α-tocopherol (Samandari E et al., (2006) Biochem Biophys Res Commun 342: 1329-33; Mazlan M et al., (2006) J Neurol Sci., 243(1-2): 5-12; Campbell S E, et al., (2006) BMC Cancer 6:13, Wu J H Y et al., (2005) Free Rad Res 39: S84-S84; Devaraj S et al., (2005) Nutr Rev 63: 290-293; Wagner K H et al. (2004) Annals Nutr Metab 48: 169-188; Jiang Q et al., (2004) Proc Natl Acad Sci U.S.A. 101: 17825-30; Grammas P et al., (2004) Biochem Biophys Res Commun 319: 1047-1052; Jiang Q et al., (2001) Am J Clin Nutr 74: 714-22) and to scavenge reactive nitrogen species such as peroxynitrite (Wolf G (1997) Nutr Rev 55: 376-378; Christen S et al., (1997) Proc Natl Acad Sci USA 94: 3217-22). The tocotrienols have been demonstrated to have significantly different biological activities from the tocopherols (Theriault A et al., (1999) Clin. Biochem. 32: 309-319), including inhibition of cholesterol biosynthesis (Parker R A et al., (1993) J Biol Chem 268: 11230-8; Pearce B C et al., (1994) J Med Chem 37: 526-41; Pearce B C et al., (1992) J Med Chem 35: 3595-606), anti-cancer effects (Nesaretnam K et al., (1998) Lipids 33: 461-469; Sylvester P W et al., (2005) Front Biosci 10: 699-709; Sylvester P W et al., (2005) J Plant Physiol 162: 803-810), and more recently for protection against glutamate-induced neurodegeneration in animal models of stroke (Khanna S et al., (2005) Stroke 36: E144-E152; Khanna S et al., (2003) J Biol Chem 278: 43508-15; Sen C K et al., (2004) Vitamin E And Health pp 127-142; Sen C K et al., (2000) J Biol Chem 275: 13049-13055).
To fully realize the promising biological activities of γ-tocopherol and the tocotrienols requires overcoming the poor bioavailability after ingestion. The primary reason for their poor bioavailability and short plasma half-lives is their rapid oxidative metabolism by tocopherol-ω-hydroxylase.
Since it has been discovered that non-α-tocopherols and the tocotrienols have desirable biological activities, there is a need to identify mechanisms that prolong their bioavailability. Based on the foregoing comments, one potential way to increase the bioavailability of non-α-tocopherols and tocotrienols is to develop compounds that decrease tocopherol-ω-hydroxylase activity.